The localization and imaging of magnetic particles and particularly nanoparticles (e.g. discrete particulate structures sized in the nanometer range) is becoming increasingly important for developing new diagnostic methods. Magnetic particles (e.g. iron oxide or iron particles having a magnetic characteristic) have recently been employed in several forms of imaging including MRI (See: H. Dahnke and T. Schaeffter: Limits of Detection of SPIO at 3.0 T Using T2 Relaxometry, Magnetic Resonance in Medicine 53:1202-1206 (2005). Recently, a relatively new method termed “Magnetic Particle Imaging” or MPI. MPI was introduced in a paper by B. Gleich and J. Weizenecker entitled Tomographic Imaging Using the Nonlinear Response of Magnetic Particles, Nature Vol. 435(30): 1214-9 Jun. 2005. Currently, this new technique (MPI) has received a good deal of attention in the wider press because of the promise of the method. See: C. Day, Novel Medical Imaging Method Shows Promise, Physics Today, Sep. 21-22, 2005. The teachings of each of the above three articles/papers being expressly incorporated herein by reference.
Thus, magnetic particles are becoming important in a wide variety of endeavors and applications. In medical applications, such magnetic particles are being used to identify pathology as well as to treat pathology like cancer and heart disease. In general, magnetic substances are relatively easy to detect using various detection and imaging technologies. A further discussion of the use of MPI, in the imaging of human bodily structures is disclosed in published U.S. Patent Application No. 2003/0085703, entitled METHOD OF DETERMINING THE SPATIAL DISTRIBUTION OF MAGNETIC PARTICLES by Bernhard Gleich, the teachings of which are expressly incorporated herein by reference. Reference will now be made to FIGS. 1 and 2, which illustrate a basic implementation of an MPI system in accordance with Gleich.
The MPI system detects particles in the field-free point 210 (FIG. 2 below) where there is very little static field. Those particles in the field free point produce signal at the harmonics, most strongly at the third harmonic.
As shown in FIG. 1, a plurality 100a, 100b of coil pairs are arranged above (100a) and beneath (100b) a patient (or other subject to be examined) 110 positioned on a table top, which is substantially non-magnetic. As described further below, the patient has been infused with magnetic nanoparticles. These particles can be formed with a variety of substances and in a range of sizes. In one example, the particles each comprise a spherical substrate, for example, of glass which is covered with a soft magnetic layer having a thickness of, for example, approximately 5 nm. This layer can consist, for example, of an iron nickel alloy (for example, permalloy). This soft magnetic layer may be covered, for example, with a further covering layer, which protects the particle against acids and other bodily fluids and/or environmental agents.
The range of these coil pairs defines the examination zone. The first coil pair includes the two identically constructed windings 102a and 102b, which are arranged coaxially above and beneath the patient or sample and conduct equally large but oppositely directed sinusoidal currents (indicated by oppositely arranged X's and dots). The gradient magnetic field thus generated can be represented by the field lines 200 shown in FIG. 2. In the direction of the (perpendicular) axis of the coil pair it has a substantially constant gradient and in a point 202 on this axis (dashed line 210) it reaches the value zero. Starting from this field-free point, the strength of the magnetic field increases in all three spatial directions as a function of the distance from this point. In a zone 210 which is denoted by a dashed circle (the first sub-zone) around the field-free point the field strength is so low that the magnetization of magnetic particles present therein is not saturated, whereas the magnetization is in a state of saturation outside the zone 210. In the zone remaining outside the zone 210 (the second sub-zone 220) the magnetization of the particles is in the saturated state.
The strength of the magnetic field required for the saturation of the magnetization of particles is dependent on their diameter and composition. Smaller particle require a larger magnetic field to saturate them than larger particles. When a coating of a material having a lower saturation magnetization is chosen, lower field values are enabled. The size of the zone 301 determines the spatial resolution of the system, and is partly dependent on the strength of the gradient of the gradient magnetic field and also on the strength of the magnetic field required for saturation. By way of example, for a 100-micron diameter and a gradient of 0.2 T/m of the magnetic field, the zone 210 (in which the magnetization of the particles is not saturated) defines a size of approximately 1 mm.
In order to appropriately image structures within the patient or other subject 100 under examination, the system must extract information concerning the spatial concentration of the magnetic particles within the subject 100. As such, a plurality of coil winding pairs is arranged above and beneath the subject 100 and/or the table top 112.
When a further magnetic field is superimposed on the gradient magnetic field in the examination zone, the zone 210 is shifted in the direction of this additional magnetic field, the extent of the shift being greater as the strength of the magnetic field is greater. When the superimposed magnetic field is variable in time, the position of the zone 210 changes accordingly in time and in space.
In order to generate such temporally variable magnetic fields for any arbitrary direction in space, three further coil winding pairs 104a and 104b, 106a and 106b, and 108a and 108b are provided coaxially with the first winding pair 102a, 102b. The coil winding pair 104a, 104b generates a magnetic field which extends in the direction of the coil axis (dashed line 130) of the coil winding pair 102a, 102b (aligned vertically in this example). To this end, the two windings 104a, 104b are supplied with equal currents which also flow in the same direction as adjacent windings 102a, 102b. The effect of coil winding pair 104a, 104b can also be achieved by superimposing currents flowing in the same direction on the oppositely directed equal currents in the coil winding pair 102a, 102b so that the current in one coil pair decreases while it increases in the other coil winding pair. However, it may be advantageous when the temporally constant gradient magnetic field and the temporally variable vertical magnetic field are generated by separate coil pairs.
In order to generate magnetic fields which extend horizontally in space in the longitudinal direction of the patient/subject 100, and also in a direction perpendicular thereto (e.g. generally parallel to the axis 130), there are provided two further coaxial coil winding pairs 106a and 106b, and 108a and 108b. In this example the coil winding pairs 106a, 106b and 108a, 108b are not of a Helmholz-type—while the coil winding pairs 102a, 102b and 104a, 104b can be of a Helmholz-type. To employ Helmholz-type coil winding pairs to generate horizontal fields would require them to be arranged along the sides of the examination zone—for example, windings each respectively arranged to the left and to the right of the examination zone and in front of and behind the examination zone. This arrangement may be impractical, as it impeded access to the examination area.
Thus, as shown, the windings 106a, 106b and 108a, 108b of the coil pairs are arranged coaxially above and beneath the examination zone, and hence they employ a winding configuration different than that of the coil winding pair 104a, 104b. Note that coils of this configuration are known and available in connection with magnetic resonance apparatus with an open magnet (e.g. open MRI) in which an RF coil pair is arranged above and beneath the examination zone so as to generate a horizontal, temporally variable magnetic field.
FIG. 1 also shows a further pickup/sensing coil(s) 150 which provides for the detection of signals generated in the examination zone. In principle any of the field-generating coil winding pairs 102a and 102b, 104a and 104b, 106a and 106b, and/or 108a and 108b can be used for this purpose. However, the use of a separate receiving coil offers advantages. A more attractive signal-to-noise ratio is obtained (notably when a plurality of receiving coils is used) and the sensing coil(s) 150 can be arranged and switched in such a manner that it is decoupled from the other coils.
In operation, the coil winding pairs 104a and 104b, 106a and 106b, and 108a and 108b receive their currents from current amplifiers 170. The variation in time of the currents Ix, Iy, and Iz which are amplified and produce the desired magnetic fields is imposed by a respective waveform generator 172. The waveform generators are controlled by a system control unit 174, which calculates the variation in time of the currents as required for the relevant examination method and loads this variation into the waveform generators. During the examination these signals are read from the waveform generators 172 and applied to the amplifiers 170, which generate the sinusoidal currents Ix, Iy, and Iz required for the coil winding pairs 104a and 104b, 106a and 106b, and 108a and 108b on the basis thereof.
Generally, a non-linear relationship exists between the shift of the zone 210 from its position at the center of the gradient coil system 102a, 102b and the current through the gradient coil system. Moreover, all three coils should generate a magnetic field when the zone 210 is to be shifted along a line extending outside the center 202. This is taken into account by the system's control unit 174 while imposing the variation in time of the currents, for example, by employing appropriate lookup tables. The zone 210, therefore, can be shifted along arbitrarily formed paths through the examination zone.
The signals S received by the sensing coil(s) 150 are applied to an amplifier 180 via a suitable filter 182. The output signals of the amplifier 180 are digitized by an analog-to-digital converter 184 so as to be applied to an image processing unit 186, which reconstructs the spatial distribution of the particles from the signals and the known position of the zone 210 during the reception of the signals S. An image of the sensed particle distribution can be displayed on an appropriate display monitor 188 (or otherwise rendered into a viewable image).
The signal produced from a harmonic field with an additional static field imposed has been characterized as discussed in Frequency Distribution of the Nanoparticle Magnetization in the Presence of a Static as Well as a Harmonic Magnetic Field, Medical Physics 35, 1988-1994, 2008, by J. B. Weaver, A. M. Rauwerdink, C. R. Sullivan, I. Baker. The second harmonic produced when there is a static field is larger than the third harmonic providing superior signal to noise. In addition, the size of the static field contributes localization information that contributes to the signal localization. See Imaging Magnetic Nanoparticles Using the Signal's Frequency Spectrum, Procedures of SPIE on Medical Imaging, Volume 6916, 6916-35, 2008, by J. B. Weaver, A. M. Rauwerdink, B. S. Trembly, C. R. Sullivan. Further, a combination of harmonic fields produce signal at many specific frequencies which can also be used to contribute localization information.
In medical applications, the ability to attach a nanoparticle to molecular agents that localize in pathology is very promising for both diagnosis and treatment. Also, a highly significant aspect of MPI is the promised sensitivity. Antibody-tagged nanoparticles can be targeted to cancer or other cells in very specific ways but highly selective targeting will generally collect relatively few nanoparticles to a specific location so sensitivity is critical. For example, targeting individual cells would be important to track a metastasis. In view of these promising new medical applications and techniques, it is, thus, highly desirable to refine the above-described system and method for performing MPI to achieve even higher imaging resolution and particle localization accuracy.